DESCRIPTION (taken from the application) Thank you for the consideration of this application for a Mentored Clinical Scientist Development Award. The applicant is a nephrologist with an interest in transplant immunology. As part of his nephrology fellowship at Brigham and Women's Hospital, the applicant completed three years of laboratory based research. The main thrust of his research was the study of the functional interactions between allogeneic endothelial cells and CD4+ T-cells. This research was funded by an individual NIH NRSA grant and the principal findings were published in the Journal of Experimental Medicine. The applicant has now completed his nephrology fellowship and has been accepted as a staff member at the Brigham and Women's Hospital and will be appointed an Instructor of Medicine at Harvard Medical School in July 2000. In this proposal, the applicant wishes to build on an earlier scientific observation that activated human endothelial cells promote the differentiation of monocytes into dendritic cells. Increasing evidence suggests that sub-populations of dendritic cells may be derived from monocytes. However the molecular signals regulating monocyte differentiation into dendritic cells, the functional characteristics of these cells in vitro and their role in antigen presentation in vivo remain unexplored. The goals of this proposal are to 1) determine the temporal pattern of gene expression that underlies monocyte differentiation into dendritic cells and identify critical genes that coordinate this process; 2) define the mechanisms by which endothelial cells promote differentiation of monocytes into dendritic cells and characterize the function of these cells in vitro; and 3) and demonstrate trafficking of circulating monocytes into tissue/lymph node dendritic cells in vivo and explore the expression of critical genes identified in the above studies using a modified human peripheral blood leukocyte-severe combined immune deficient (PBL-Hu-SCID) mouse model of human skin transplantation. The applicant appreciates that in order to further explore his recent preliminary findings he needs additional training. The Mentored Clinical Scientist Development Award will provide the crucial means for training in DNA microarray, bioinformatics and transfection technology necessary for achieving independence. The Sponsors' laboratories provide an ideal environment to accomplish the aims of this project because of their strong scientific background, the collaborative momentum that has been achieved and their exemplary didactic and ethical curriculum. After completing this project the applicant will return to immunological research and competitively examine the in vivo function of monocyte derived dendritic cells in renal transplantation.